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A cholesterol-free, high-fat diet suppresses gene expression of cholesterol transporters in murine small intestine

A cholesterol-free, high-fat diet suppresses gene expression of cholesterol transporters in... Transporters present in the epithelium of the small intestine determine the efficiency by which dietary and biliary cholesterol are taken up into the body and thus control whole-body cholesterol balance. Niemann-Pick C1 Like Protein 1 (Npc1l1) transports cholesterol into the enterocyte, whereas ATP-binding cassette transporters Abca1 and Abcg5/Abcg8 are presumed to be involved in cholesterol efflux from the enterocyte toward plasma HDL and back into the intestinal lumen, respectively. Abca1 , Abcg5 , and Abcg8 are well-established liver X receptor (LXR) target genes. We examined the effects of a high-fat diet on expression and function of cholesterol transporters in the small intestine in mice. Npc1l1 , Abca1 , Abcg5 , and Abcg8 were all downregulated after 2, 4, and 8 wk on a cholesterol-free, high-fat diet. The high-fat diet did not affect biliary cholesterol secretion but diminished fractional cholesterol absorption from 61 to 42% ( P < 0.05). In an acute experiment in which triacylglycerols of unsaturated fatty acids were given by gavage, we found that this downregulation occurs within a 6-h time frame. Studies in LXRα-null mice, confirmed by in vitro data, showed that fatty acid-induced downregulation of cholesterol transporters is LXRα independent and associated with a posttranslational increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity that reflects induction of cholesterol biosynthesis as well as with a doubling of neutral fecal sterol loss. This study highlights the induction of adaptive changes in small intestinal cholesterol metabolism during exposure to dietary fat. cholesterol absorption; ABC transporters; Npc1l1; fatty acids Address for reprint requests and other correspondence: N. de Wit, Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen Univ., Bomenweg 2, NL-6703 HD, Wageningen, the Netherlands (e-mail: nicole.dewit@wur.nl ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Gastrointestinal and Liver Physiology The American Physiological Society

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References (53)

Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
0193-1857
eISSN
1522-1547
DOI
10.1152/ajpgi.00360.2007
pmid
18356535
Publisher site
See Article on Publisher Site

Abstract

Transporters present in the epithelium of the small intestine determine the efficiency by which dietary and biliary cholesterol are taken up into the body and thus control whole-body cholesterol balance. Niemann-Pick C1 Like Protein 1 (Npc1l1) transports cholesterol into the enterocyte, whereas ATP-binding cassette transporters Abca1 and Abcg5/Abcg8 are presumed to be involved in cholesterol efflux from the enterocyte toward plasma HDL and back into the intestinal lumen, respectively. Abca1 , Abcg5 , and Abcg8 are well-established liver X receptor (LXR) target genes. We examined the effects of a high-fat diet on expression and function of cholesterol transporters in the small intestine in mice. Npc1l1 , Abca1 , Abcg5 , and Abcg8 were all downregulated after 2, 4, and 8 wk on a cholesterol-free, high-fat diet. The high-fat diet did not affect biliary cholesterol secretion but diminished fractional cholesterol absorption from 61 to 42% ( P < 0.05). In an acute experiment in which triacylglycerols of unsaturated fatty acids were given by gavage, we found that this downregulation occurs within a 6-h time frame. Studies in LXRα-null mice, confirmed by in vitro data, showed that fatty acid-induced downregulation of cholesterol transporters is LXRα independent and associated with a posttranslational increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity that reflects induction of cholesterol biosynthesis as well as with a doubling of neutral fecal sterol loss. This study highlights the induction of adaptive changes in small intestinal cholesterol metabolism during exposure to dietary fat. cholesterol absorption; ABC transporters; Npc1l1; fatty acids Address for reprint requests and other correspondence: N. de Wit, Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen Univ., Bomenweg 2, NL-6703 HD, Wageningen, the Netherlands (e-mail: nicole.dewit@wur.nl )

Journal

AJP - Gastrointestinal and Liver PhysiologyThe American Physiological Society

Published: May 1, 2008

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